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Theory predicts that we can protect the efficacy of
future antimalarials by changing treatment practice or
drug formulation, but the potential success of such
interventions rests upon their impact on drug pressure
in the field. So far, gathering field data on the relationship
between policy, drug pressure, recombination and
the evolution of resistance has been entirely challenging.
To test these predictions, dhfr and dhps frequency
changes were measured in two rural districts of Rufiji
and Kilombero/Ulanga during 2000-2006, and the frequencies
of the two genes compared prior, during and
after antimalarial policy change from first line CQ to
first line SP in 2001. Furthermore, while SP first line
was maintained in Kilombero/Ulanga, pilot combination
therapy of SP+Artesunate (ART) was introduced in
Rufiji in 2002 to replace SP and dhfr and dhps frequency
changes compared between the two districts. Size polymorphisms
at three sets of microsatellite loci linked to
dhfr and three other sets of unlinked microsatellite loci
were analysed. Genetic analysis of SP resistance genes
was carried out on 9,662 Plasmodium falciparum infections
identified in a series of annual cross sectional surveys
conducted in the two districts between 2000-2006.
The frequency of dhfr and dhps resistance alleles did
not change significantly while SP was the recommended
second-line treatment, but highly significant changes
occurred during the subsequent year after the switch to
first line SP. The frequency of the triple mutant dhfr
allele increased by 37% -63% and that of double mutant
dhps allele increased 200%-300%. A strong association
between these unlinked alleles also emerged; confirming
that they are co-selected by SP. Distribution of major
lineages indicates that there is extensive genetic
exchange among the geographic regions. Combination
therapy had visible effect on the frequencies of dhfr and
dhps resistance alleles. The findings of this study provide
insight on the interplay between policy, drug pressure,
recombination and the evolution of resistance. |
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